Genetic mapping of developmental trajectories for complex traits and diseases

Abstract

Genome-wide association studies (GWAS) have identified numerous common genetic variants associated with complex human traits and diseases. However, the translation of GWAS discoveries into biological and clinical insights is highly challenging. In this study, we present a novel bioinformatics approach for enhancing the functional interpretation of GWAS signals, based on their integration with single-cell (sc)RNA-seq datasets that examine developmental processes. Our approach performs three tasks: (1) Identification of links between cell differentiation trajectories and traits; (2) Elucidation of biological processes and molecular pathways that underlie such trajectory-trait links; and (3) Prioritization of target genes that carry the links between trajectories, pathways and traits. We applied our method to a set of 11 traits of various pathologies, and 12 scRNA-seq datasets of diverse developmental processes, and it readily detected well-established biological connections, including those between the maturation of cortical inhibitory interneurons and schizophrenia, hepatocytes and cholesterol levels, and pancreatic beta-islet cells and type-2 diabetes. For each of these associations, our method pinpointed top candidate genes that are strongly associated with both the kinetics of the differentiation trajectory and the disease’s genetic risk. By the identification of trajectory-disease links, molecular pathways that underlie them and prioritizing candidate risk genes, our method improves the understanding of the etiology of complex diseases, and thus holds promise for enhancing rational drug development that is aimed at targeting specific biological processes that mediate the genetic predisposition to diseases.